Not applicable.
This invention relates to novel quinones. The invention also relates to conjugates of quinones with various peptides. The invention also relates to various medicinal and industrial uses of these compounds, including the use of these compounds in treating diseases such as cancer.
The quinones are a large and varied group of natural products found in all major groups of organisms. Quinones are a group of aromatic dioxo compounds derived from benzene or multiple-ring hydrocarbons such as naphthalene, anthracene, etc. They are classified as benzoquinones, naphthoquinones, anthraquinones, etc., on the basis of the ring system. The Cxe2x95x90O groups are generally ortho or para, and form a conjugated system with at least two Cxe2x95x90C double bonds; hence the compounds are colored, yellow, orange or red. Quinones with long isoprenoid side chains, such as plastoquinone, ubiquinone and phytoquinone are involved in the basic life processes of photosynthesis and respiration. Quinones are biosynthesized from acetate/malonate via shikimic acid. A few quinones are used as laxatives and worming agents, and others are used a pigments in cosmetics, histology and aquarrell paints. Quinones have a variety of medicinal and industrial uses.
Many efficient antineoplastic drugs are either quinones (anthracycline derivatives, mitoxantrone, actinomycin), quinonoid derivatives (quinolones, genistein, bactracyclin), or drugs such as etoposide that can easily be converted to quinones by in vivo oxidation. Gantchev et al. (1997) Biochem. Biophys. Res. Comm. 237:24-27. The literature on quinone-DNA interactions is replete with references to quinones having the potential to undergo redox cycling with the formation of highly reactive oxygen species that are thought to relate to their cytotoxicity. O""Brien (1991) Chem. Biol. Interactions 80:1-41. It has also been shown that many quinones are efficient modifiers of the enzymatic activity of topoisomerase II, an enzyme essential for cell division.
Quinones are now widely used as anti-cancer, anti-bacterial and anti-malarial drugs, as well as fungicides. The antitumor activities of the quinones were revealed more than two decades ago when the National Cancer Institute published a report in which fifteen-hundred synthetic and natural quinones were screened for their anticancer activities. Driscoll et al. (1974) Cancer Chemot. Reports 4:1-362. Anti-cancer quinones include xcex2-Lapachone, a plant product, which inhibits DNA topoisomerase II and induces cell death with characteristics of apoptosis in human prostate and promyelocytic leukemia cancer cell lines. Human breast and ovary carcinoma showed sensitivity of the cytotoxic effect of xcex2-lapachone without signs of apoptosis. Li et al. (1995) Cancer Res. 55:3712-5; and Planchon et al. (1995) Cancer Res. 55:3706-11. 1,2-Naphthoquinone (3,4-b)dihydrofuran inhibits neoplastic cell growth and proliferation of several cancers, such as prostate, breast, colon, brain and lung, including multi-drug resistant types. WO 97/31936. Furano-naphthoquinone derivatives and other naphthoquinones and naphth-[2,3-d]-imidazole-4,9-dione compounds are also useful in treating malignant tumors such as those affecting the blood, breast, central nervous system, cervix, colon, kidney, lung, prostate and skin. WO 97/30022 and JP Patent No. 9235280. Anthraquinone derivatives with telomerase inhibitory activity are also useful in treating leukemia, lung cancer, myeloma, lymphoma, prostate, colon, head and neck, melanoma, hepatocellular carcinoma, bladder, ovarian, breast and gastric cancers. WO 98/25884 and WO 98/25885. Ansamycin benzoquinones are useful in the treatment of primitive neuroectodermal tumors, prostate cancer, melanoma and metastatic Ewing""s sarcoma. WO 94/08578.
Quinones also have a number of other medicinal uses. Terpenoid-type quinones are also useful as treatments for diabetes. U.S. Pat. No. 5,674,900. Additional quinones can be used to treat cirrhosis and other liver disorders. U.S. Pat. Nos. 5,210,239 and 5,385,942. Hydroquinone amines and quinone amines are also useful for treating a number of conditions, including spinal trauma and head injury. U.S. Pat. No. 5,120,843. Degenerative central nervous system diseases, as well as vascular diseases, are treatable with quinones such as Idebenone [2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone] and Rifamycin S. Mordente et al. (1998) Chem. Res. Toxicol. 11:54-63; Rao et al. (1997) Free Radic. Biol. Med 22:439-46; Cortelli et al. (1997) J. Neurol. Sci. 148:25-31; and Mahadik et al. (1996) Prostaglandins Leukot. Essent. Fatty Acids 55:45-54. A vitamin K analog, 6-cyclo-octylamino-5,8-quinoline quinone shows efficacy for treatment of leprosy and tuberculosis. U.S. Pat. No. 4,963,565. Hydroquinone is used to treat skin pigmentation disorders. Clarys et al. (1998) J. Dermatol. 25:412-4. Mitomycin C-related drug indoloquinone EO9 has demonstrated cell killing against HL-60 human leukemia cells, H661 human lung cancer cells, rat Walker tumor cells and human HT29 colon carcinoma cells. Begleiter et al. (1997) Oncol. Res. 9:371-82; and Bailey et al. (1997) Br. J. Cancer 76:1596-603. Quinones such as aloin, a C-glycoside derivative of anthraquinone, accelerate ethanol oxidation and may be useful in treating acute alcohol intoxication. Chung et al. (1996) Biochem. Pharmacol. 52:1461-8 and Nanji et al. (1996) Toxicol. Appl. Pharmacol. 140:101-7. Quinones capsaicin and resiniferatoxin blocked activation of nuclear transcription factor NF-xcexaB, which is required for viral replication, immune regulation and induction of various inflammatory and growth-regulatory genes. Singh et al. (1996) J. Immunol. 157:4412-20. Antiretroviral and antiprotozoan naphthoquinones are described in U.S. Pat. Nos. 5,780,514 and 5,783,598. Anthraquinones are also useful as laxatives. Ashraf et al. (1994) Aliment. Pharmacol. Ther. 8:329-36; and Muller-Lissner (1993) Pharmacol. 47 (Suppl. 1): 138-45.
A subset of quinones designated lapachones has been shown to have activity against neoplastic cells, as described in U.S. Pat. Nos. 5,969,163, 5,824,700, and 5,763,625. Antiviral activity (in combination with xanthine) or reverse transcriptase inhibitory activity for xcex2-lapachone is suggested in U.S. Pat. Nos. 5,641,773 and 4,898,870, while antifungal and trypanosidal activity of xcex2-lapachone is suggested in U.S. Pat. Nos. 5,985,331 and 5,912,241.
Quinones can be administered alone or in conjunction with other agents, such as 1,2-dithiole-3-thione. Begleiter et al. (1997). Hydroxyquinone can be used in conjunction with glycol or glyceryl esters of retinoic acid to treat skin disorders. WO 9702030. Combinational chemotherapy of carboquone, a benzoquinine derivative, and cis-Platinum, diminishes the side effects of the former. Saito (1988) Gan To"" Kagaku Ryoho 15:549-54.
Quinones also have various additional uses. A few quinones are used as laxatives and worming agents, and others are used a pigments in cosmetics, histology and aquarrell paints. Quinones include 2,5-cyclohexadiene-1,4-dione, which is useful as an oxidizing agent; in photography (U.S. Pat. No. 5,080,998); in manufacturing dyes and hydroquinone; in tanning hides; in strengthening animal fibers; and as a reagent.
In rapidly dividing cells such as tumor cells, cytotoxicity due to quinone administration has been attributed to DNA modification. However the molecular basis for the initiation of quinone cytotoxicity in resting or non-dividing cells has been attributed to the alkylation of essential protein thiol or amine groups and/or the oxidation of essential protein thiols by activated oxygen species and/or GSSG, glutathione disulfide. Oxidative stress arises when the quinone is reduced by reductases to a semiquinone radical which reduces oxygen to superoxide radicals and reforms the quinone. This futile redox cycling and oxygen activation forms cytotoxic levels of hydrogen peroxide and GSSG is retained by the cell and causes cytotoxic mixed protein disulfide formation. O""Brien (1991) Chem. Biol. Interact. 80:1-41.
Conjugation of quinones and glutathione (GSH) are sometimes associated with the process of detoxification. Jeong et al. (1996) Mol. Pharmacol. 50:592-8. For example, certain o-quinones contribute to the neurodegenerative processes underlying Parkinson""s disease and schizophrenia. Glutathione transferase (GST) M2-2, which conjugates glutathione and o-quinones, prevents these processes. Baez et al. (1997) Biochem. J. 324:25-8. However, in many cases, conjugation with GSH actually leads to quinone bioactivation and toxicity. For example, the nephrotoxicity of hydroquinone and bromobenzene is mediated via quinone-glutathione conjugates. Jeong et al. (1996) Mol. Pharmacol. 50:592-8. The formation of GSH conjugates is also involved in the bioactivation of vicinal dihalopropane 1,2-dibromo-3-chloropropane. Hinson et al. (1995) Can. J. Physiol. Pharm. 73:1407-13. Additional examples of GSH conjugation potentiating the toxicity of quinones are described in Fowler et al. (1991) Hum. Exp. Toxicol. 10:451-9; Mertens et al. (1991) Toxicol. Appl. Pharmacol. 110:45-60; Puckett-Vaughn et al. (1993) Life Sci. 52:1239-47; Dekant (1993) Toxicol. Lett. 67:151-160; Monks et al. (1994) Chem. Res. Toxicol. 7:495-502; Monks (1995) Drug Metab. Rev. 27:93-106; and Eyer (1994) Environ. Health Persp. 102 (Suppl. 6):123-32.
Because of the wide variety of biological processes in which quinones play a critical role, it would be advantageous to develop novel quinones for various uses, including disease treatment.
All references cited herein are hereby incorporated by reference in their entirety.
The invention provides novel quinone compounds and methods for use of the quinone compounds in treating diseases.
In one embodiment, the invention comprises compounds of the formula 
wherein A is selected from the group consisting of xe2x80x94Oxe2x80x94 and xe2x80x94CH2xe2x80x94; wherein M1 is selected from the group consisting of a single bond and C1-C8 alkyl, C1-C8 branched alkyl, C3-C8 cycloalkyl, and C3-C8 cycloaryl; wherein B is selected from the group consisting of xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94; xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94, and xe2x80x94N(R1)xe2x80x94; wherein R1 is selected from the group consisting of xe2x80x94H, C1-C8 alkyl, C1-C8 branched alkyl, C3-C8 cycloalkyl, and C3-C8 cycloaryl; wherein M2 is selected from the group consisting of a single bond and C1-C8 alkyl, C1-C8 branched alkyl, C3-C8 cycloalkyl, and C3-C8 cycloaryl; wherein D is selected from the group consisting of xe2x80x94H, xe2x80x94OH, xe2x80x94N(R7)(R8), pentoses, hexoses, 
wherein R4 is selected from the group consisting of xe2x80x94H, C1-C8 alkyl, C1-C8 branched alkyl, C3-C8 cycloalkyl, C3-C8 cycloaryl, xe2x80x94N(R9)(R10), and xe2x80x94CN; and wherein R7, R8, R9 and R10 are independently selected from the group consisting of xe2x80x94H, C1-C8 alkyl, C1-C8 branched alkyl, C3-C8 cycloalkyl, C3-C8 cycloaryl, and 
The invention also comprises the above compounds in combination with a pharmaceutically acceptable carrier. The invention also comprises use of the above compounds to treat an indication characterized by the proliferation of disease cells in an individual, comprising administering to the individual a therapeutic amount of one or more of the above compounds, optionally together with another therapeutically effective compound or compounds.
In another embodiment, the invention comprises compounds of the formula 
wherein x is an integer between 1 and 2; and each K is independently selected from the group consisting of H, C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkanol, C1-C8 alkoxy, 
and where zero or two, but no more than two, vicinal K""s in the molecule represent single electrons which form a pi bond, thus forming a double bond together with the existing sigma bond between the two adjacent carbons bearing the two vicinal K""s.
The invention also comprises the above compounds in combination with a pharmaceutically acceptable carrier. The invention also comprises use of the above compounds to treat an indication characterized by the proliferation of disease cells in an individual, comprising administering to the individual a therapeutic amount of one or more of the above compounds, optionally together with another therapeutically effective compound or compounds.
In another embodiment, the invention comprises compounds of the formula 
wherein R is selected from the group consisting of C1-C8 alkyl, C1-C8 cycloalkyl, C3-C8 cycloaryl, C1-C8 branched alkyl, and C1-C8 alkanol. The invention also comprises the above compounds in combination with a pharmaceutically acceptable carrier. The invention also comprises use of the above compounds to treat an indication characterized by the proliferation of disease cells in an individual, comprising administering to the individual a therapeutic amount of one or more of the above compounds, optionally together with another therapeutically effective compound or compounds.
In another embodiment, the invention comprises compounds of the formula 
wherein Y is selected from the group consisting of xe2x80x94H, xe2x80x94F, xe2x80x94Br, xe2x80x94Cl, and xe2x80x94I; and wherein G1 and G2 are independently selected from the group consisting of H, C1-C8 alkyl, 
and xe2x80x94C(xe2x95x90O)xe2x80x94CHnX3-n, where n is an integer from 0 to 3 and X is selected from the group consisting of F, Cl, Br, and I. The invention also comprises the above compounds in combination with a pharmaceutically acceptable carrier. The invention also comprises use of the above compounds to treat an indication characterized by the proliferation of disease cells in an individual, comprising administering to the individual a therapeutic amount of one or more of the above compounds, optionally together with another therapeutically effective compound or compounds.
In another embodiment, the invention comprises compounds of the formula 
wherein M is selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94(Cxe2x95x90O)xe2x80x94 xe2x80x94C(xe2x95x90O)xe2x80x94Nxe2x80x94, and xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94. The invention also comprises the above compounds in combination with a pharmaceutically acceptable carrier. The invention also comprises use of the above compounds to treat an indication characterized by the proliferation of disease cells in an individual, comprising administering to the individual a therapeutic amount of one or more of the above compounds, optionally together with another therapeutically effective compound or compounds.
In another embodiment, the invention comprises compounds of the formula 
wherein x is an integer between 1 and 2; each B is independently selected from the group consisting of H, C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 cycloaryl, C1-C8 alkyl-C3-C8 cycloalkyl, and C1-C8 alkyl-C3-C8 cycloaryl; and each K is independently selected from the group consisting of H, OH, C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkanol, C1-C8 alkoxy, and where zero or two, but no more than two, vicinal K""s in the molecule represent single electrons which form a pi bond, thus forming a double bond together with the existing sigma bond between the two adjacent carbons bearing the two vicinal K""s. The invention also comprises the above compounds in combination with a pharmaceutically acceptable carrier. The invention also comprises use of the above compounds to treat an indication characterized by the proliferation of disease cells in an individual, comprising administering to the individual a therapeutic amount of one or more of the above compounds, optionally together with another therapeutically effective compound or compounds.
In another embodiment, the invention comprises compounds of the formula 
wherein each B is independently selected from the group consisting of H, C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 cycloaryl, C1-C8 alkyl-C3-C8 cycloalkyl, and C1-C8 alkyl-C3-C8 cycloaryl; and wherein R is selected from the group consisting of C1-C8 alkyl and C1-C8 alkanol. The invention also comprises the above compounds in combination with a pharmaceutically acceptable carrier. The invention also comprises use of the above compounds to treat an indication characterized by the proliferation of disease cells in an individual, comprising administering to the individual a therapeutic amount of one or more of the above compounds, optionally together with another therapeutically effective compound or compounds.
In another embodiment, the invention comprises compounds of the formula 
where M5 is C1-C8 alkyl, y is an integer from 1 to 6, and L is selected from the group consisting of xe2x80x94Oxe2x80x94K1 or xe2x80x94N(K1K2); where K1 and K2 are independently selected from the group consisting of H, C1-C8 alkyl, C1-C8 alkyl-COOH, C1-C8 alkyl-COOxe2x80x94C1-C8 alkyl, C1-C8 alkyl-N(G1G2), and C1-C8 alkyl-N(G3)-C1-C8 alkyl-N(G4G5); and wherein each of G1, G2, G3, G4, and G5 is independently selected from the group consisting of H and C1-C8 alkyl. The invention also comprises the above compounds in combination with a pharmaceutically acceptable carrier. The invention also comprises use of the above compounds to treat an indication characterized by the proliferation of disease cells in an individual, comprising administering to the individual a therapeutic amount of one or more of the above compounds, optionally together with another therapeutically effective compound or compounds.
In another embodiment, the invention comprises compounds of the formula 
where z is an integer between one and ten; G10 is selected from the group consisting of C1-C8 alkyl; each M is independently selected from the group consisting of C1-C8 alkyl; each V is selected from the group consisting of xe2x80x94C(xe2x95x90O)xe2x80x94Nxe2x80x94 and xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94; and T is selected from the group consisting of xe2x80x94COOM8 and xe2x80x94CONM9M10, where each of M8, M9 and M10 are independently selected from the group consisting of H and C1-C8 alkyl. The invention also comprises the above compounds in combination with a pharmaceutically acceptable carrier. The invention also comprises use of the above compounds to treat an indication characterized by the proliferation of disease cells in an individual, comprising administering to the individual a therapeutic amount of one or more of the above compounds, optionally together with another therapeutically effective compound or compounds.
In another embodiment, the invention comprises compounds of the formula 
where M12 is selected from the group consisting of C1-C8 alkyl.
In another embodiment, the invention comprises compounds of the formula 
where M14 and M15 are independently selected from the group consisting of C1-C8 alkyl. The invention also comprises the above compounds in combination with a pharmaceutically acceptable carrier. The invention also comprises use of the above compounds to treat an indication characterized by the proliferation of disease cells in an individual, comprising administering to the individual a therapeutic amount of one or more of the above compounds, optionally together with another therapeutically effective compound or compounds.
In another embodiment, the invention comprises compounds of the formula 
where J is selected from the group consisting of C1-C8 alkyl, C1-C8 cycloalkyl, C3-C8 cycloaryl, and C1-C8 branched alkyl. The invention also comprises the above compounds in combination with a pharmaceutically acceptable carrier. The invention also comprises use of the above compounds to treat an indication characterized by the proliferation of disease cells in an individual, comprising administering to the individual a therapeutic amount of one or more of the above compounds, optionally together with another therapeutically effective compound or compounds.
In another embodiment, the invention comprises compounds of the formula 
where RS is the side chain of a naturally-occuring amino acid. The invention also comprises the above compounds in combination with a pharmaceutically acceptable carrier. The invention also comprises use of the above compounds to treat an indication characterized by the proliferation of disease cells in an individual, comprising administering to the individual a therapeutic amount of one or more of the above compounds, optionally together with another therapeutically effective compound or compounds.
In another embodiment, the invention embraces compounds of the formula S-L-QUIN, where S represents a single amino acid or a peptide of at least two amino acids, L is a linking group containing at least one carbon, oxygen, or nitrogen atom attached covalently to both S and QUIN, or a nonentity; and QUIN is a quinone, quinone derivative, hydroquinone, or hydroquinone derivative. In a preferred embodiment, S or a portion thereof, S-L or a portion thereof, or both S or a portion thereof and then L or a portion thereof, are cleaved from the quinone-containing remainder of the molecule by an enzyme, such as the enzyme prostate specific antigen. In another preferred embodiment, L is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94NHxe2x80x94(C1-C8 alkyl)xe2x80x94Oxe2x80x94. In yet another preferred embodiment, L is xe2x80x94NHxe2x80x94(C6H4)CH2xe2x80x94Oxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94(C1-C8 alkyl)xe2x80x94Oxe2x80x94. A preferred peptide for the S moiety is X-Ser-Lys-Leu-Gln, where X is a protecting group or an amino-terminal capping group, and the side chains of Ser, Lys, and Gln may optionally be protected with protecting groups. The invention also comprises the above compounds in combination with a pharmaceutically acceptable carrier. The invention also comprises use of the above compounds to treat an indication characterized by the proliferation of disease cells in an individual, comprising administering to the individual a therapeutic amount of one or more of the above compounds, optionally together with another therapeutically effective compound or compounds.
The invention also embraces compounds of the formula S-L-QUIN, wherein S represents a single amino acid or a peptide of at least two amino acids; L is a linking group containing at least one carbon, oxygen, or nitrogen atom attached covalently to both S and QUIN, or a nonentity; and QUIN is selected from the group consisting of the any of the above-mentioned quinone compounds which have a reactive group capable of being conjugated with an amino or carboxyl group, as well as the compounds 
The invention also comprises the above compounds in combination with a pharmaceutically acceptable carrier. The invention also comprises use of the above compounds to treat an indication characterized by the proliferation of disease cells in an individual, comprising administering to the individual a therapeutic amount of one or more of the above compounds, optionally together with another therapeutically effective compound or compounds.
The invention also encompasses a method for making the above-described compounds of formula S-L-QUIN, comprising the steps of a) covalently linking L to S, and b) covalently linking L to QUIN. Steps a) and b) can be performed in either order or simultaneously.
The invention also encompasses compounds of the formula 
where x is an integer between 1 and 2; W is selected from xe2x80x94H, xe2x80x94OH, xe2x80x94Oxe2x80x94C1-C8 alkyl, xe2x80x94Oxe2x80x94C1-C8 alkyl-NH2, and xe2x80x94Oxe2x80x94C1-C8 alkyl-NHxe2x80x94S, wherein S is a single amino acid or a peptide of two or more amino acids; and each K is independently selected from the group consisting of H, OH, C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkanol, C1-C8 alkoxy, and where zero or two, but no more than two, vicinal K""s in the molecule represent single electrons which form a pi bond, thus forming a double bond together with the existing sigma bond between the two adjacent carbons bearing the two vicinal K""s. In a preferred embodiment, W is xe2x80x94Oxe2x80x94C1-C8 alkyl-NHxe2x80x94S, S is a single amino acid or a peptide of two or more amino acids; and the group xe2x80x94NHxe2x80x94 forms an amide bond with the alpha-carboxy group of S when S is a single amino acid. Alternatively, the group xe2x80x94NHxe2x80x94 forms an amide bond with the C-terminal alpha-carboxy group of S when S is a peptide of two or more amino acids. A preferred subset of the above compounds are the compounds of the formula 
where W is selected from xe2x80x94H, xe2x80x94OH, xe2x80x94Oxe2x80x94C1-C8 alkyl, xe2x80x94Oxe2x80x94C1-C8 alkyl-NH2, and xe2x80x94Oxe2x80x94C1-C8 alkyl-NHxe2x80x94S, and wherein S is a single amino acid or a peptide of two or more amino acids. In a preferred embodiment, W is xe2x80x94Oxe2x80x94C1-C8 alkyl-NHxe2x80x94S, S is a single amino acid or a peptide of two or more amino acids, and the group xe2x80x94NHxe2x80x94 forms an amide bond with the alpha-carboxy group of S when S is a single amino acid. Alternatively, the group xe2x80x94NHxe2x80x94 forms an amide bond with the C-terminal alpha-carboxy group of S when S is a peptide of two or more amino acids. The invention also comprises the above compounds in combination with a pharmaceutically acceptable carrier. The invention also comprises use of the above compounds to treat an indication characterized by the proliferation of disease cells in an individual, comprising administering to the individual a therapeutic amount of one or more of the above compounds, optionally together with another therapeutically effective compound or compounds.
The invention also includes all salts, stereoisomers, and tautomers of the foregoing compounds, unless explicitly indicated otherwise.
In another embodiment, the invention comprises any one or more of the foregoing compounds, optionally in combination with another therapeutic compound, combined with a pharmaceutically acceptable excipient or carrier.
The invention also provides methods of treating an indication comprising the step of administering to the individual an effective amount of a composition comprising a novel quinone. In one embodiment, the invention comprises a method of treating an indication characterized by the proliferation of disease cells in an individual comprising administering to the individual a therapeutic amount of any of the foregoing compounds. In one method, the indication is cancer. In various embodiments, the cancer affects cells of the bladder, blood, brain, breast, colon, digestive tract, lung, ovaries, pancreas, prostate gland, or skin. In other embodiments, the indication can also include, but is not limited to, Alzheimer""s disease, epilepsy, multiple sclerosis, problems associated with tissue grafts and organ transplants, psoriasis, restenosis, stomach ulcers, or tissue overgrowth after surgery. In other embodiments, the indication is an infection or infestation of parasites, bacteria, fungi or insects.